Project Summary Progress to define mechanisms of white matter injury (WMI) in vascular cognitive impairment and dementia (VCID) has been hampered by fundamental gaps in our understanding of the vascular and glial mechanisms related to the pathogenesis of remyelination failure, a hallmark of VCID. We propose a highly integrated analysis of the interplay between microvascular and oligodendrocyte progenitor cell (OPC) contributions to VCID pathogenesis. We will mechanistically link dysfunctional reactivity and inflammation of the WM vasculature to novel perivascular disturbances in OPC responses to WMI that appear central to myelination failure in VCID. We will test the over-riding hypothesis that dysfunction of white matter arterioles establishes selectively vulnerable zones of perivascular WMI from oxidative and nitrosative stress that result in functionally dysmature white matter niches associated with aberrant OPC migration, proliferation and differentiation to myelinating oligodendrocytes. This hypothesis is supported by our recent studies (Bagi et al., Ann Neurol 2018; 83:142-152) that identified selectively impaired vasodilator function of human WM penetrating arterioles in microvascular brain injury (mVBI) in similar white matter regions where disrupted maturation of pre-myelinating OPCs occurred. In all three aims, we will employ a unique collection of human rapid autopsy brains from a large cohort of cases with VCID where white matter hyperintensities (WMHs) were identified by ante-mortem MRI. Although WMHs are widely used clinically to identify patients at risk for cognitive decline, their pathological basis is poorly defined. In aim 1, we will define mechanistic relationships among impaired cholinergic vasodilation of white matter arterioles, high vascular wall shear stress and WMI arising from augmented production of reactive oxygen and nitrogen species. We will test the hypothesis that impaired cholinergic vasodilation exposes endothelial cells in WM penetrating arterioles to a high level of wall shear stress, which induces augmented production of reactive oxygen and nitrogen species in mVBI. In aim 2, we will define molecular disturbances in the OPC-vascular niche that contribute to myelination failure in mVBI. We will focus on the role of vascular factors in aberrant OPC migration, proliferation and maturation. We will capitalize on several new lines of data that demonstrate novel perivascular injury responses of OPCs at the level of WM arterioles and capillaries. In aim 3, we will define vascular extracellular matrix mechanisms related to hyaluronic acid (HA)-mediated dysfunction of WM arterioles. We will integrate approaches using murine and human vessels to define the role of various forms of HA in vascular inflammation, loss of vascular integrity and abnormal leukocyte adhesion and extravasation across the vascular endothelium. Our over-riding objective is to provide a mechanistic molecular explanation for the distinct OPC-vascular processes that render aging human white matter particularly susceptible to microvascular WMI in order to develop therapies that promote remyelination in chronic WMI.